IL-15 and IL-2 are two structurally and functionally related cytokines whose high affinity receptors share the IL-2R b-chain and g-chain in association with IL-15R a-chain (IL-15Ra) or IL-2R a-chain, respectively. Whereas IL-2 action seems restricted to the adaptative T cells, IL-15 appears to be crucial for the function of the innate immune responses, and the pleiotropic expression of IL-15 and IL-15Ra hints at a much broader role for the IL-15 system in multiple cell types and tissues. In this report, using a highly sensitive radioimmunoassay, we show the existence of a soluble form of human IL-15Ra (sIL-15Ra) that arises from proteolytic shedding of the membrane-anchored receptor. This soluble receptor is spontaneously released from IL-15Ra-expressing human cell lines as well as from IL-15Ra transfected COS-7 cells. This release is strongly induced by PMA and ionomycin, and to a lesser extent by IL-1b and TNF-a. The size of sIL-15Ra (42 kDa), together with the analysis of deletion mutants in the ectodomain of IL-15Ra, indicates the existence of cleavage sites that are proximal to the plasma membrane. Whereas shedding induced by PMA was abrogated by the synthetic matrix metalloproteinases inhibitor GM6001, the spontaneous shedding was not, indicating the occurrence of at least two distinct proteolytic mechanisms. The sIL-15Ra displayed high affinity for IL-15 and behaved as a potent and specific inhibitor of IL-15 binding to the membrane receptor, and of IL-15-induced cell proliferation (IC 50 in the range from 3 to 20 pM). These results suggest that IL-15Ra shedding may play important immunoregulatory functions.